This invention relates to solid pharmaceutical compositions containing pregabalin which are suitable for once daily (QD) oral dosing.
Pregabalin, or (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid, binds to the alpha-2-delta (α2δ) subunit of a calcium channel and is related to the endogenous inhibitory neurotransmitter γ-aminobutyric acid (GABA), which is involved in the regulation of brain neuronal activity. Pregabalin exhibits anti-seizure activity, as discussed in U.S. Pat. No. 5,563,175 to R. B. Silverman et al., and is useful for treating, among other conditions, epilepsy, pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, fibromyalgia, and various psychiatric disorders, including anxiety, depression, mania, and bipolar disorder. In the United States, pregabalin has been approved for the treatment of diabetic peripheral neuropathy, postherpetic neuralgia, and as an adjunctive treatment for partial onset seizures in adults. Pregabalin is available as an immediate release (IR) formulation in capsules and is administered to patients two- or three-times daily (BID or TID).
Many patients receiving pregabalin or other drugs which are administered two or more times daily would likely benefit from once daily dosing. The convenience of QD dosing generally improves patient compliance, especially for elderly patients and for patients taking multiple medications. Once per day dosing may also lessen or prevent potentially undesirable dose-related effects by reducing peak blood levels (CMAX) and may also increase drug efficacy by increasing minimum plasma concentrations (CMIN).
Once daily dosing of pregabalin, however, presents numerous challenges. Conventional extended release (ER) compositions are problematic for QD dosing because pregabalin is not absorbed uniformly in the gastrointestinal (GI) tract. Clinical studies indicate that pregabalin is absorbed in the small intestine and the ascending colon in humans, but is poorly absorbed beyond the hepatic flexure. This suggests that the mean absorption window for pregabalin is, on average, about six hours or less—any drug release from a conventional ER dosage form beyond six hours would thus be wasted because the dosage form has traveled beyond the hepatic flexure. Furthermore, pregabalin is a γ-amino acid which under normal storage conditions may undergo intramolecular cyclization to form a lactam, 4-isobutyl-pyrrolidin-2-one. See, e.g., WO 99/10186 and WO 99/59573, both to A. Aomatsu. Although it is known that the non-active components of the pharmaceutical composition may affect lactam formation, it is difficult to predict which excipients may lead to undesirable lactam formation.